Preparation method of didrogesterone

Abstract

The invention discloses a preparation method of didrogesterone, which comprises the following steps: by using 3, 20-bis (ethylenedioxy)-19-norpregna-5 (10), 9 (11) diene as an initial raw material, carrying out epoxidation, methylation, hydrogenation, one-pot hydrolysis, hydroxyl removal and dehydrogenation to obtain the didrogesterone. The preparation method is feasible in operation, low in cost and high in product purity, and has remarkable economic benefits when being applied to industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of steroid drug preparation, in particular to a method for preparing dydrogesterone. Background Art

[0002] The chemical structure of dydrogesterone is very similar to progesterone in nature, except that the 10th methyl group is in the α position (the natural one is in the β position) and the 9th hydrogen atom is in the β position (the natural one is in the α position). Studies have found that steroid compounds with 9β, 10α structures have significant effects on physiological properties compared with steroid compounds with 9α, 10β structures. At present, dydrogesterone is widely used to maintain pregnancy, prevent miscarriage and treat various diseases caused by endogenous progesterone deficiency. Since it was launched globally in 1961, it has a large global sales market. Therefore, the research and development of its synthesis technology has very important economic and social value. The main preparation methods reported so far are as follows.

[0003] Westerhof et al. used luminosterol as the starting material and obtained the target product dydrogesterone through Oppenauer oxidation, isomerization, catalytic hydrogenation, ozonation, addition, sodium dichromate oxidation and dehydrogenation reactions. However, luminosterol does not exist in nature, and it is necessary to artificially synthesize luminosterol through ergosterol through photoreaction, which has high energy consumption and great production safety risks (Recueil, 1960, 79: 771-783.).

[0004] Chinese patent document CN101318982A discloses a photoisomerization reaction using 3-acetoxy-pregnane-5,7-diene-20-one as a starting material. However, there are two carbonyl groups in the 3-acetoxy-pregnane-5,7-diene-20-one molecule. After being excited by light, this type of compound can generate more impurities, and the actual yield is greatly reduced.

[0005] The document Recueil des Travaux Chimiques des Pays-Bas (1971), 90:27-32 reported a method for obtaining dydrogesterone by protecting diketone with ethylene glycol, brominating, debrominating, irradiating with high-pressure mercury lamp, and hydrolyzing and rearranging from progesterone. However, this route has a low yield in two steps due to the presence of many isomers in bromination and debromination, and the key irradiation step has high energy consumption and high safety risks. Therefore, the industrialization cost of this preparation method is also relatively high.

[0006] The above methods for preparing dydrogesterone all require photoreaction to achieve chiral inversion at the 9,10 positions, and therefore have the problems of high energy consumption, high production safety risk, and high cost. Summary of the invention

[0007] The invention provides a method for preparing dydrogesterone, so as to solve the defects in the existing process for preparing dydrogesterone, that the steps are long, the yield is low and the photoreaction is involved, which is not conducive to large-scale industrial production.

[0008] In view of this, the scheme of the present invention is:

[0009] A method for preparing dydrogesterone, comprising the steps of:

[0010] S1. Compound 1 is subjected to epoxidation reaction using hydrogen peroxide in the presence of a base and a first catalyst to obtain compound 2;

[0011] S2. Compound 2 undergoes a Grignard addition reaction under the action of methylmagnesium bromide to obtain compound 3;

[0012] S3. Compound 3 undergoes a hydrogenation reaction with hydrogen under the action of a second catalyst to obtain compound 4;

[0013] S4. Compound 4 is deprotected from ketal and hydroxyl groups under acidic conditions, and then dehydrogenated by dichlorocyanobenzoquinone to obtain dydrogesterone;

[0014] The reaction route of the preparation method is as follows:

[0015]

[0016] In a preferred embodiment, in step S1:

[0017] The first catalyst is preferably hexachloroacetone;

[0018] And / or, the base is pyridine, and the volume ratio of the base to compound 1 is (0.05-0.15):1;

[0019] And / or, the content of hydrogen peroxide is 50%, and the volume ratio of hydrogen peroxide to compound 1 is (0.2-0.4):1;

[0020] And / or, the temperature of the reaction process is -15 to -20°C;

[0021] And / or, the solvent used in the reaction process is dichloromethane.

[0022] Step S1 also includes a product post-treatment step: the reaction product is first allowed to stand for separation, the organic layer is washed with a saturated salt solution, the solvent is evaporated after water absorption and drying, and the compound 2 is obtained by crystallization, filtration and drying.

[0023] In some embodiments, based on the above steps, the yield of compound 2 obtained in step S1 can reach 70%.

[0024] In a preferred embodiment, in step S2:

[0025] The molar ratio of the compound 2 to methyl magnesium bromide is 1:(3-4);

[0026] And / or, the reaction temperature is -5 to 5°C, and the reaction process is carried out under an inert atmosphere;

[0027] And / or, the solvent used in the reaction process is tetrahydrofuran.

[0028] Step S2 also includes a product post-treatment step: after the reaction is completed, the temperature is controlled below 0°C to quench the reaction, the organic layer is washed and dehydrated with saturated brine, the solvent is evaporated, and then crystallization, filtration, and drying are performed to obtain compound 3.

[0029] In some embodiments, based on the above steps, the yield of compound 3 obtained in step S2 can reach 70%.

[0030] In a preferred embodiment, in step S3:

[0031] The second catalyst is palladium on carbon;

[0032] And / or, the reaction temperature is 30-40°C, and the reaction pressure is 0.1-0.3Mpa;

[0033] The solvent used in the reaction is tetrahydrofuran.

[0034] Furthermore, step S3 also includes a product post-treatment step: filtering after the reaction is completed, washing the filtrate with solvents in sequence, then washing with a saturated salt solution, and then drying and evaporating the solvent to obtain compound 4.

[0035] In some embodiments, based on the above steps, the yield of compound 4 obtained in step S3 can reach 90%.

[0036] In a preferred embodiment, during the ketal removal and hydroxyl reaction described in step S4:

[0037] The reaction temperature is 80-85°C and the reaction time is 0.5-2h;

[0038] And / or, the solvent used is dioxane.

[0039] In a preferred embodiment, during the dehydrogenation reaction in step S4:

[0040] The reaction temperature is 30-40°C;

[0041] And / or, the mass ratio of the compound 4 to dichlorocyanobenzoquinone is 1:(0.55-0.58).

[0042] Step S4 also includes a product post-treatment step: after the dehydrogenation reaction is completed, the organic layer is allowed to stand and separated, the organic layer is washed with saturated sodium carbonate and saturated brine in sequence, and then the solvent is evaporated, crystallized, filtered, and dried to obtain dydrogesterone.

[0043] In some embodiments, based on the above steps, the yield of dydrogesterone obtained in step S4 can reach 55%.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] The preparation method of the present invention uses 3,20-bis(ethylenedioxy)-19-norpregna-5(10),9(11)diene as a starting material, and prepares dydrogesterone through epoxidation, methylation, hydrogenation, and one-pot hydrolysis, dehydroxylation and dehydrogenation. The preparation method is feasible to operate, has low cost, and has high product purity, and has significant economic benefits when applied to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 The HPLC spectrum of dydrogesterone obtained by the preparation method of the present invention is shown in FIG.

[0047] Figure 2 The figure is the mass spectrum of dydrogesterone obtained by the preparation method of the present invention.

[0048] Figure 3 The figure is the hydrogen nuclear magnetic resonance spectrum of dydrogesterone obtained by the preparation method of the present invention. DETAILED DESCRIPTION

[0049] The technical solution of the present invention will be clearly and completely described below in conjunction with the preferred embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0050] In the following examples, the compound 1, named 3,20-bis(ethylenedioxy)-19-norpregnane-5(10),9(11)diene, with CAS number 101387-15-9, can be prepared from the compound (CAS: 1231-97-6) was prepared.

[0051] Example 1

[0052] 1) Dissolve 100g of compound 1 (3,20-bis(ethylenedioxy)-19-norpregnane-5(10),9(11)diene) in 1L of dichloromethane, pour into a reaction bottle, cool to -15°C, add 10mL of pyridine, 30mL of hexachloroacetone, and 30mL of hydrogen peroxide in sequence, control the temperature at -15°C for reaction, and perform TLC detection. After the reaction is complete, perform post-treatment. Pour the reaction solution into a separatory funnel and let it stand for ten minutes. Separate the liquid, wash the organic layer once with 500mL of saturated sodium thiosulfate solution, and then wash it once with 500mL of saturated sodium chloride solution. Dry the washed organic layer with 10g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is evaporated, add 200mL of ethyl acetate, stir at 0°C for crystallization, filter, and dry to obtain 65g of compound 2, with a weight yield of 65%.

[0053] 2) Add 65g of compound 2 to a reaction bottle, stir and dissolve with 650mL of tetrahydrofuran, add 6.5g of lithium chloride, replace with nitrogen three times, lower the temperature to -5°C, drop 240mL of methylmagnesium bromide in tetrahydrofuran solution (1mol / L), control the temperature at -5°C for reaction, detect by TLC, and perform post-treatment after the reaction is complete. Control the temperature at -5 to 0°C, drop 650mL of water into the reaction solution, let stand for stratification, and wash the organic layer once with 650mL of saturated sodium chloride solution. Dry the washed organic layer with 6.5g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled out, add 65mL of ethyl acetate, stir and crystallize at 0°C, filter, and dry to obtain 45g of compound 3, with a weight yield of 69.2%.

[0054] 3) Add 45g of compound 3 to a hydrogenation reactor, stir and dissolve with 450mL of tetrahydrofuran, add 1.35g of palladium carbon, replace with nitrogen 3 times, heat to 30°C, stir and react with hydrogen pressure of 0.2MPa, detect by TLC, and perform post-treatment after the reaction is complete. Filter, wash the filter cake with 45mL of tetrahydrofuran, and wash the filtrate once with 450mL of saturated sodium chloride solution. Dry the washed organic layer with 4.5g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is evaporated, and dry to obtain 39g of compound 4, with a weight yield of 86.6%.

[0055] 4) Add 39g of compound 4 to the reaction bottle, add 390mL of dioxane and stir, then add 45mL of dioxane solution of hydrogen chloride (4mol / L), heat to 80℃ and react for 1h, then cool to 30℃, add 22.5g of dichlorocyanobenzoquinone, control the temperature to 30℃ and react, detect by TLC, and perform post-treatment after the reaction is complete. Add 390mL of dichloromethane, then add 390mL of water and stir for 1h, then let stand to separate, the organic layer is first washed once with 390mL of saturated sodium carbonate solution, and then washed once with 390mL of saturated sodium chloride solution. Dry the washed organic layer with 3.9g of anhydrous sodium sulfate and distill under reduced pressure until no solvent is evaporated. Use 39mL of ethyl acetate and 78mL of cyclohexane, stir at 5℃ to crystallize, filter, and dry to obtain 21.5g of dydrogesterone, with a weight yield of 55.1%. The HPLC spectrum of the obtained dydrogesterone is as follows Figure 1 As shown, the purity was 99.97%, and the total yield based on compound 1 was 26.59%.

[0056] The obtained mass spectrum and hydrogen nuclear magnetic resonance spectrum of dydrogesterone are as follows: Figure 2 , Figure 3 The hydrogen spectrum and mass spectrum data of dydrogesterone are as follows:

[0057] 1 HNMR (400 MHz, CDCl 3 )δ6.20-6.14(m, 2H, -CH=×2), 5.68(s, 1H, -CH=), 2.61-2.51(m, 2H), 2.47-2.39(m, 2H), 2.30-2.17(m, 2H), 2.14(s, 3H, -CH 3 ), 2.03-1.95(m, 2H), 1.89-1.61(m, 7H), 1.39-1.32(m, 1H), 1.31(s, 3H, -CH 3 ), 0.71(s, 3H, -CH 3 );

[0058] MS(m / z)calcd for C 21 H 28 O 2 (M+H) + 313, found 313.

[0059] Example 2

[0060] 1) Dissolve 100g of compound 1 (3,20-bis(ethylenedioxy)-19-norpregnane-5(10),9(11)diene) in 1L of dichloromethane, pour into a reaction bottle, cool to -20°C, add 10mL of pyridine, 30mL of hexachloroacetone, and 30mL of hydrogen peroxide in sequence, control the temperature at -20°C for reaction, and perform TLC detection. After the reaction is complete, perform post-treatment. Pour the reaction solution into a separatory funnel and let it stand for ten minutes. Separate the liquid, wash the organic layer once with 500mL of saturated sodium thiosulfate solution, and then wash it once with 500mL of saturated sodium chloride solution. Dry the washed organic layer with 10g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is evaporated, add 200mL of ethyl acetate, stir at 5°C for crystallization, filter, and dry to obtain 66g of compound 2, with a weight yield of 66%.

[0061] 2) Add 66g of compound 2 to a reaction bottle, stir and dissolve with 660mL of tetrahydrofuran, add 6.6g of lithium chloride, replace with nitrogen three times, lower the temperature to 5°C, drop 244mL of methylmagnesium bromide tetrahydrofuran solution (1mol / L), control the temperature to react at 5°C, detect by TLC, and perform post-treatment after the reaction is complete. Control the temperature at -5 to 0°C, drop 660mL of water into the reaction solution, let stand and separate, and wash the organic layer once with 660mL of saturated sodium chloride solution. Dry the washed organic layer with 6.6g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled out, add 66mL of ethyl acetate, stir and crystallize at 5°C, filter, and dry to obtain 44g of compound 3, with a weight yield of 66.6%.

[0062] 3) Add 44g of compound 3 to a hydrogenation reaction kettle, stir and dissolve with 440mL of tetrahydrofuran, add 1.32g of palladium carbon, replace with nitrogen 3 times, heat to 40°C, stir and react with hydrogen pressure of 0.2MPa, detect by TLC, and perform post-treatment after the reaction is complete. Filter, wash the filter cake with 44mL of tetrahydrofuran, and wash the filtrate once with 440mL of saturated sodium chloride solution. Dry the washed organic layer with 4.4g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is evaporated, and dry to obtain 38g of compound 4, with a weight yield of 86.3%.

[0063] 4) Add 38g of compound 4 to the reaction bottle, add 380mL of dioxane and stir, then add 43mL of hydrogen chloride in dioxane solution (4mol / L), heat to 85℃ and react for 1h, then cool to 40℃, add 21.3g of dichlorocyanobenzoquinone, control the temperature at 40℃ and react, detect by TLC, and perform post-treatment after the reaction is complete. Add 380mL of dichloromethane, then add 380mL of water and stir for 1h, then stand and separate, the organic layer is first washed once with 380mL of saturated sodium carbonate solution, and then washed once with 380mL of saturated sodium chloride solution. Dry the washed organic layer with 3.8g of anhydrous sodium sulfate and distill under reduced pressure until no solvent is evaporated. Use 38mL of ethyl acetate and 76mL of cyclohexane, stir and crystallize at 10℃, filter, and dry to obtain 20.2g of dydrogesterone, with a weight yield of 53.1%. The HPLC purity is 99.95%, and the total yield is 24.99% based on compound 1.

[0064] Example 3

[0065] 1) Dissolve 100g of compound 1 (3,20-bis(ethylenedioxy)-19-norpregnane-5(10),9(11)diene) in 1L of dichloromethane, pour into a reaction bottle, cool to -18°C, add 10mL of pyridine, 30mL of hexachloroacetone, and 30mL of hydrogen peroxide in sequence, control the temperature at -18°C for reaction, and perform TLC detection. After the reaction is complete, perform post-treatment. Pour the reaction solution into a separatory funnel and let it stand for ten minutes. Separate the liquid, wash the organic layer once with 500mL of saturated sodium thiosulfate solution, and then wash it once with 500mL of saturated sodium chloride solution. Dry the washed organic layer with 10g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is evaporated, add 200mL of ethyl acetate, stir at 0°C for crystallization, filter, and dry to obtain 64g of compound 2, with a weight yield of 64%.

[0066] 2) Add 64g of compound 2 to a reaction bottle, stir and dissolve with 640mL of tetrahydrofuran, add 6.4g of lithium chloride, replace with nitrogen three times, lower the temperature to 0°C, drop 236mL of methylmagnesium bromide tetrahydrofuran solution (1mol / L), control the temperature to react at 0°C, detect by TLC, and perform post-treatment after the reaction is complete. Control the temperature at -5 to 0°C, drop 640mL of water into the reaction solution, let stand and separate, and wash the organic layer once with 640mL of saturated sodium chloride solution. Dry the washed organic layer with 6.4g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled out, add 64mL of ethyl acetate, stir and crystallize at 3°C, filter, and dry to obtain 43.5g of compound 3, with a weight yield of 68%.

[0067] 3) Add 43.5g of compound 3 to a hydrogenation reaction kettle, stir and dissolve with 435mL of tetrahydrofuran, add 1.29g of palladium carbon, replace with nitrogen 3 times, heat to 35°C, stir and react with hydrogen pressure of 0.2MPa, detect by TLC, and perform post-treatment after the reaction is complete. Filter, wash the filter cake with 43mL of tetrahydrofuran, and wash the filtrate once with 435mL of saturated sodium chloride solution. Dry the washed organic layer with 4.3g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is evaporated, and dry to obtain 37.8g of compound 4, with a weight yield of 86.9%.

[0068] 4) Add 37.8g of compound 4 to the reaction bottle, add 378mL of dioxane and stir, then add 43mL of hydrogen chloride dioxane solution (4mol / L), heat to 83℃ and react for 1h, then cool to 35℃, add 21.3g of dichlorocyanobenzoquinone, control the temperature at 35℃ and react, detect by TLC, and perform post-treatment after the reaction is complete. Add 378mL of dichloromethane, then add 378mL of water and stir for 1h, then stand and separate, the organic layer is first washed once with 378mL of saturated sodium carbonate solution, and then washed once with 378mL of saturated sodium chloride solution. Dry the washed organic layer with 3.7g of anhydrous sodium sulfate and distill under reduced pressure until no solvent is evaporated. Use 38mL of ethyl acetate and 76mL of cyclohexane, stir and crystallize at 8℃, filter, and dry to obtain 20.8g of dydrogesterone, with a weight yield of 55%. The HPLC purity is 99.96%, and the total yield is 25.73% based on compound 1.

[0069] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing dydrogesterone, characterized in that the steps include: S1. Compound 1 is subjected to epoxidation reaction using hydrogen peroxide in the presence of a base and a first catalyst to obtain compound 2; S2. Compound 2 undergoes a Grignard addition reaction under the action of methylmagnesium bromide to obtain compound 3; S3. Compound 3 undergoes a hydrogenation reaction with hydrogen under the action of a second catalyst to obtain compound 4; S4. Compound 4 is deprotected from ketal and hydroxyl groups under acidic conditions, and then dehydrogenated by dichlorocyanobenzoquinone to obtain dydrogesterone; The reaction route of the preparation method is as follows:

2. The preparation method according to claim 1, characterized in that: In step S1, the first catalyst is hexachloroacetone; And / or, the base is pyridine, and the volume ratio of the base to compound 1 is (0.05-0.15):1; And / or, the content of hydrogen peroxide is 50%, and the volume ratio of hydrogen peroxide to compound 1 is (0.2-0.4):1; And / or, the temperature of the reaction process is -15 to -20°C; And / or, the solvent used in the reaction process is dichloromethane.

3. The preparation method according to claim 1, characterized in that: In step S1, the reaction product is first allowed to stand for separation, the organic layer is washed with a saturated salt solution, the solvent is evaporated after absorption and drying, and the compound 2 is obtained by crystallization, filtration and drying.

4. The preparation method according to claim 1, characterized in that: In step S2, the molar ratio of the compound 2 to methyl magnesium bromide is 1:(3-4); And / or, the reaction temperature is -5 to 5°C, and the reaction process is carried out under an inert atmosphere; And / or, the solvent used in the reaction process is tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that: In step S2, after the reaction is completed, the temperature is controlled below 0°C to quench the reaction, the organic layer is washed and dehydrated with saturated brine, the solvent is evaporated, and then crystallization, filtration, and drying are performed to obtain compound 3.

6. The preparation method according to claim 1, characterized in that: In step S3, the second catalyst is palladium on carbon; And / or, the reaction temperature is 30-40°C, and the reaction pressure is 0.1-0.3Mpa; And / or, the solvent used in the reaction is tetrahydrofuran.

7. The preparation method according to claim 1, characterized in that: In step S3, after the reaction is completed, the reaction is filtered, and the filtrate is sequentially washed with a solvent, and then washed with a saturated salt solution, and then the solvent is evaporated after being dried to obtain compound 4.

8. The preparation method according to claim 1, characterized in that: In the process of removing ketal protection and hydroxyl group reaction in step S4: the reaction temperature is 80-85° C., the reaction time is 0.5-2 h, and / or the solvent used is dioxane.

9. The preparation method according to claim 1, characterized in that: In the dehydrogenation reaction process of step S4: the reaction temperature is 30-40° C., and / or the mass ratio of the compound 4 to dichlorocyanobenzoquinone is 1:(0.55-0.58).

10. The preparation method according to claim 1, characterized in that: In step S4, after the dehydrogenation reaction is completed, the organic layer is allowed to stand and separated, and the organic layer is washed with saturated sodium carbonate and saturated brine in sequence, and then the solvent is evaporated, crystallized, filtered, and dried to obtain dydrogesterone.

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